RET-altered Thyroid & Lung Cancers

RET-altered thyroid and lung cancers are driven by genetic changes in the RET (rearranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase involved in cell growth and differentiation. In thyroid cancer, RET alterations manifest primarily as activating point mutations in medullary thyroid carcinoma (MTC) and as RET gene fusions in papillary thyroid carcinoma (PTC) and other forms. Germline or somatic RET mutations occur in about 50% of sporadic MTC cases and nearly all hereditary MTC, while RET fusions are observed in 5–10% of papillary thyroid cancers, with higher incidence in pediatric cases.

In non-small cell lung cancer (NSCLC), RET fusions are found in roughly 1–2% of patients, commonly involving fusion partners like KIF5B and CCDC6. RET fusion-positive NSCLC typically affects younger, non-smoking patients and often presents with peripheral lung tumors and brain metastases.

The advent of selective RET inhibitors, such as selpercatinib and pralsetinib, has revolutionized treatment for these cancers, showing high response rates and durable efficacy with better tolerability compared to earlier multikinase inhibitors. These targeted therapies are effective regardless of tumor origin, exemplifying precision medicine's tumor-agnostic approach. However, resistance to RET inhibitors can develop, driven by on-target mutations or off-target mechanisms, highlighting the need for ongoing research into combination therapies and new agents.

Detecting RET alterations through next-generation sequencing and other molecular diagnostics is essential for guiding therapy, improving outcomes, and personalizing treatment in RET-driven thyroid and lung cancers.